CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size

Ludwig, Anna L.; Espinal, Glenda; Pretto, Dalyir; Jamal, Amanda L.; Arqué, Glòria; Tassone, Flora; Berman, Robert F.; Hagerman, Paul J.

doi:10.1093/hmg/ddu032

Cited by 66 publications

(74 citation statements)

References 66 publications

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“…Indeed, autism is uniquely human and there are only a few validated animal models (e.g., fmr1 knockout mice, BTBR mice, and valproic acid-treated rats), that display autistic-like features. Fragile X syndrome (FXS) is an inherited disorder caused by mutations in FMR1, which is translated into the fragile X mental retardation 1 protein, which, in turn, plays a role in the development of synapses [97,98]. Expansion mutations of FMR1 produce autistic features in approximately 40 % of patients with FXS, and thus FXS provides a valuable model for identifying novel biomarkers/targets for autism and for dissecting the underlying neurochemical pathways [99].…”

Section: Alterations Of the Ecb System In Autismmentioning

confidence: 99%

Endocannabinoid Signaling in Autism

et al. 2015

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Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the Bendocannabinoid (eCB) system^, a rather complex ensemble of lipid signals (Bendocannabinoids^), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD.Key Words Autism spectrum disorder . endocannabinoid system . fragile X syndrome . metabolic regulation . reward system The Endocannabinoid SystemTwenty-five years after the cloning and expression of a complementary DNA that encoded a G protein-coupled receptor, named type-1 cannabinoid (CB 1 ) receptor [1], there is a good deal of information on the main components of the so-called Bendocannabinoid (eCB) system^, as well as on its role in controlling cannabinergic signaling in human health and disease [2][3][4]. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most active eCBs as yet identified, although this family of bioactive lipids includes other arachidonic acid (AA) derivatives with cannabimimetic properties (i.e., noladin ether, virodhamine, N-arachidonoyldopamine, to name but a few). The classical dogma that eCBs are synthesized and released Bon demand^upon (patho)physiological stimuli has been recently revisited on the basis of unexpected evidence for intracellular reservoirs and transporters of eCBs. These new entities have been shown to drive intracellular trafficking of eCBs, adding a new dimension to the regulation of their biological activity [5]. To date, several metabolic routes have B. Chakrabarti, A. Persico and N. Battista are equal first authors.

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Section: Alterations Of the Ecb System In Autismmentioning

confidence: 99%

Endocannabinoid Signaling in Autism

et al. 2015

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“…As the premutation increases from 55 to 200, the level of FMR1 mRNA increases and the levels of FMRP begin to decline (115,116). Reduced FMR1 translation is observed in adult individuals with large size premutation alleles (> 110 CGG repeats) and these individuals can have cognitive deficits.…”

Section: Premutation Genotypesmentioning

confidence: 99%

Fragile X spectrum disorders

Lozano

Rosero²,

Hagerman

2014

IRDR

157

110

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“…The values of FMRP correlate inversely with CGG repeat number in the PM (decrease with increased number of CGG repeats starting roughly after ~120 triplets [52] due to a deficit in translational efficiency [53]. FMRP is widely expressed throughout the embryonic brain development and its expression levels increase during neuronal differentiation [54].…”

Section: Neurobiological Features and Targeted Treatments In Fragile mentioning

confidence: 99%

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Budimirović¹,

Duy²

2015

Engrami

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SummaryFragile X syndrome (FXS) is the leading known monogenetic cause of autism spectrum disorder (ASD) and inherited form of intellectual disability (ID). As the major and growing public health problem worldwide, ASD is purely behaviorally defined whereas FXS is a medical/genetic disorder characterized by ID and ASD in males and learning and behavioral/emotional problems (social anxiety, attention network) in both genders. FXS is caused by a mutation in the Fragile X Mental Retardation 1 gene (FMR1) that leads to the epigenetic silencing of the gene and absence of its encoded protein, the fragile X mental retardation protein (FMRP). FMRP selectively targets approximately 4% of the transcribed mRNAs in the brain. Namely, to date, 842 such target mRNAs in mammalian brains have been identified and many of them converge on the same pathway as nonsyndromic ASD. Thus, FXS is the most studied 'disorder of synapse' model for syndromic ASD in the field of neuroscience. There are currently no effective treatments for either FXS or ASD.In this review article, we discuss recent progress and future directions in translating breakthrough preclinical findings that reveal potential therapeutic targets into clinical trials for humans with FXS of potential relevance for ASD. To date, a total of 20 double-blinded, randomized, placebo-controlled clinical trials in FXS have been identified through the FDA ClinicalTrial.gov website. The majority of these trials were completed between 2008−2015. These mostly phase II trials in adults and adolescents tested 13 compounds and have primarily targeted excitatory/inhibitory imbalance theory of FXS and ASD, namely a reversal of social/behavioral symptoms that are part of the core FXS phenotype but not the core synaptic dysfunction in FXS. Despite much progress in the field propelled by the preclinical advances, these clinical studies illustrate the gaps and challenges of translating therapies from animal models to humans with FXS and ASD ('building a bridge and walking on it'). Specifically, recent challenges in the clinical trials demonstrate the need to study for longer period of time (6−12 months), prepubertal age group(s), develop more objective clinical outcome measures (i.e., clinician-based, relevant learning paradigms, and desired biomarkers), and longer placebo run-ins to minimize the placebo impact for both FXS and ASD. Ultimately, a truly satisfactory FXS, and ASD, therapy may likely involve a combination of drugs (and learning paradigms), each targeting a different aspect of the core synaptic, cognitive and behavioral impairments in FXS.

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CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size

Cited by 66 publications

References 66 publications

Endocannabinoid Signaling in Autism

Endocannabinoid Signaling in Autism

Fragile X spectrum disorders

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

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